Erectile dysfunction is a serious and common complication of diabetes mellitus. Apart from peripheral actions of corporal smooth muscle relaxation, the activation of sympathetic and parasympathetic nerves involved central mechanisms are also responsible for penile erection. We have shown that 1) in rats with streptozotocin (STZ)-induced type I diabetes (T1D) the erectile response to central administrated N-methyl-D-aspartic acid (NMDA) in the PVN is blunted, 2) NMDA-induced erection is nitric oxide (NO)-mediated, 3) neuronal NO synthase (nNOS) in the PVN of T1D rats is reduced, 4) replacing nNOS specifically in the PVN (via adenoviral-mediated gene transfer) restores the NMDA- induced erection in T1D rats, 5) plasma levels of angiotensin II (Ang II) are increased and Ang II type 1 (AT1) receptors in the PVN are up-regulated in T1D rats, 6) Ang II modulates autonomic outflow via a reactive oxygen species (ROS), particularly superoxide (O2-) mechanism, 7) Ang II down-regulates nNOS in cultured neuronal cells. Exciting preliminary results obtained in our laboratory suggest that exercise training (ExT) dramatically improves central NMDA-induced erectile response in T1D. Based on these intriguing preliminary data and previous work, the present project will attempt to address the hypothesis that ExT improves central NMDA- induced erectile dysfunction in T1D rats by regulating NO and Ang II-O2- signaling pathways in the PVN. In Aim 1 we will determine the impact of ExT on central NMDA-NO-induced erectile dysfunction in T1D rats. In Aim 2 we will determine the contribution of Ang II to central NMDA-NO- induced erectile dysfunction in T1D rats. In Aim 3 we will determine if the enhanced Ang II contributes to central NMDA-NO-induced erectile dysfunction in T1D rats via stimulation of O2-. In Aim 4 we will determine if ExT has beneficial effects on central NMDA-NO-induced erectile dysfunction through the actions on Ang II-O2- signaling in the PVN of T1D rats. These aims will be addressed in T1D rats using complementary methodologies in the whole animal to the cellular level; physiological measurement of erectile function, microinjection of the PVN in conscious and anesthetized animals, adenoviral gene transfection, O2- and NO metabolite measurements, immunohistochemistry, molecular biology techniques to measure mRNA message using real time PCR and Western blot to measure the protein within specific brain nuclei. The successful completion of the proposed studies should provide significant new information regarding the central mechanisms, specifically within the PVN of the hypothalamus, involved in altered neural regulation of erectile function and the therapeutic benefits of ExT on erectile dysfunction in T1D. Understanding the role of central mechanisms, (not much studied to date), in the altered neural drive would enhance our ability to treat the diabetic sexual dysfunction. PUBLIC HEALTH RELEVANCE: Erectile dysfunction is a serious and common complication of diabetes mellitus. The proposed mechanisms for erectile dysfunction in diabetes include both peripheral and central abnormalities However, in diabetic male patients sildenafil (Viagra) appears to be therapeutic only in 50% of the patients at the level of the penis. The proposed studies should provide significant new information regarding the central mechanisms involved in altered neural regulation of erectile function and the therapeutic benefits of exercise training on erectile dysfunction in diabetes. Understanding the role of central mechanisms, (not much studied to date), in the altered neural drive would enhance our ability to treat the diabetic sexual dysfunction.